Breast Imaging Studies in Women at High Genetic Risk of Breast Cancer: Annual Follow-Up Study

Background:

- Women who carry mutations in genes such as BRCA1/2 have a higher lifetime risk of breast
cancer (BC) and are at risk of developing BC at earlier ages than women in the general
population.

- Prophylactic mastectomy and/or oophorectomy may be used to decrease risk and intensified
mammographic and magnetic resonance imaging (MRI) surveillance may allow earlier
diagnosis; however, prophylactic mastectomy has not been shown to convey survival
advantage over more conservative management.

- Greater breast tissue density and low BC incidence result in a lower positive predictive
value of mammography in premenopausal women as compared to postmenopausal women
(PPV=0.04 for women aged 40-49).

- This study explores whether high-risk breast imaging phenotypes may be identified by
comparing imaging characteristics of mutation carriers/non-carriers using two imaging
modalities: mammography and MRI.

- Nipple Aspiration Fluid collection (NAF) and breast duct lavage will be used to obtain
cytologic materials which may be used as an adjunct to breast imaging for the early
detection of epithelial atypia and pre-invasive cancer.

Objectives:

- Compare four outcomes including two mammographic density measures (qualitative and
semiquantitative), fibroglandular volume measure using MRI, and contrast enhancement
measure using MRI (both semiquantitative) in mutation carriers/non-carriers to improve
lesion detection

- Explore non-ionizing approaches (MRI) to BC screening because the effects of ionizing
radiation due to mammography are unknown.

- Use NAF and/or BDL to obtain epithelial cell samples and correlate cytologic and imaging
findings.

- Gather prospective data on the transformation from
normal/hyperplastic/pre-invasive/invasive disease in BRCA1/2 mutation
carriers/non-carriers through molecular/genetic studies of breast tissue (via biopsy of
radiographic abnormalities) or breast fluid (via BDL and/or nipple aspiration) and
develop molecular markers for early detection of epithelial atypia/pre-invasive cancer.

- Assess the psychosocial impact of participation in a BC screening program.

Eligibility:

- Women 25-56 years of age carrying a known BRCA1/2 deleterious mutation.

- Women between the ages of 25 -56 who are first- or second- degree relatives of
individuals with a deleterious BRCA1/2 mutation.

- Women aged 25-56 who are first- or second- degree relatives of individuals with
BRCA-associated cancers in families with documented BRCA mutations.

Design:

- Prospective cohort study of 200 women to gather data on the evolution of epithelial
cell/molecular changes in BRCA1/2 mutation carriers, by collecting/analyzing NAF, BDL
fluid, biopsy tissues (when indicated), and serum/lymphocytes; samples are stored for
future studies.

- Women complete questionnaires and undergo breast/pelvis examination, transvaginal
ultrasonography, serum pregnancy test, fasting glucose, electrolytes, BUN, creatinine
and CA 125. Standard four view mammogram and breast MRI are performed on study entry and
annually for three additional years.

- INCLUSION CRITERIA - Annual Follow-up Study:

To participate in the Annual Follow-up Study, a woman must:

Be at least 25 years of age (or 5 years younger than the age at diagnosis of the youngest
family member with a tumor associated with the Breast-Ovarian Cancer Syndrome) and less
than 56 years of age.

Must be:

A known BRCA1 or BRCA2 deleterious mutation carrier

OR

A first- or second- degree relative of an individual known to carry a deleterious BRCA1 or
BRCA2 mutation

OR

A first- or second- degree relative of an individual with a tumor associated with the
Breast-Ovarian Cancer Syndrome in a family with a known BRCA mutation.

Have undergone genetic counseling and risk assessment.

Agree to release of genetic test result for stratification purposes, whether or not she has
chosen to receive individual test results for clinical decision-making.

Have an ECOG performance status of 0-1.

Be able to provide informed consent.

Have at least one non-irradiated breast.

EXCLUSION CRITERIA - Annual Follow-up Study:

Any of the following will result in exclusion from the Annual Follow-up Study:

Pregnancy or lactation within 6 months of enrollment.

Abnormal CA-125 level.

Bilateral breast cancer, ovarian (any stage) or breast cancer (Stage IIB or worse) unless
relapse free for 5 years prior to the time of enrollment.

Patients with DCIS, Stage I and Stage II breast cancer are eligible provided that it has
been at least 6 months from the completion of primary therapy (surgery, radiation, and
chemotherapy as applicable). Tamoxifen and aromatase inhibitor adjuvant therapy is allowed.

Patients with DCIS, Stage I and Stage II breast cancer who have had a local relapse after
primary treatment are not eligible unless they have been relapse free for 5 years prior to
the time of enrollment.

History of other invasive cancer unless relapse free for 5 years prior to the time of
enrollment. Non-Melanoma skin cancer or cervical carcinoma in situ are excepted.

Previous bilateral mastectomy or bilateral radiation therapy.

Weigh over 136 kilograms.

Allergy to gadolinium.

Allergy to lidocaine or Marcaine (bupivacaine). (excluded from breast duct lavage only).

Subareolar or other surgery of the breast to be studied which might disrupt the ductal
systems. For example, papilloma resection, biopsy or fine needle aspirations (FNAs) within
2 cm of the nipple might disrupt the ductal systems. Biopsies or FNAs greater than 2 cm
from the nipple are acceptable. (Excluded from ductal lavage only)

A breast implant or prior silicone injections in the breast to be studied. (Exclude from
breast ductal lavage only)

Active infections or inflammation in a breast to be studied. (breast ductal lavage only)

Medical or psychiatric disorder which, in the opinion of the Principal Investigator, would
preclude informed consent or ability to participate in clinical research.